CN103483255B - Fluorinated isoquinoline compounds and preparation method thereof - Google Patents

Fluorinated isoquinoline compounds and preparation method thereof Download PDF

Info

Publication number
CN103483255B
CN103483255B CN201210194986.1A CN201210194986A CN103483255B CN 103483255 B CN103483255 B CN 103483255B CN 201210194986 A CN201210194986 A CN 201210194986A CN 103483255 B CN103483255 B CN 103483255B
Authority
CN
China
Prior art keywords
preparation
silver
fluorinated
aryl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201210194986.1A
Other languages
Chinese (zh)
Other versions
CN103483255A (en
Inventor
刘国生
徐涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN201210194986.1A priority Critical patent/CN103483255B/en
Publication of CN103483255A publication Critical patent/CN103483255A/en
Application granted granted Critical
Publication of CN103483255B publication Critical patent/CN103483255B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses a class of fluorinated isoquinoline compounds and a preparation method thereof. The fluorinated isoquinoline compound has the following structural general formula, wherein R1-R5 are respectively and independently selected from hydrogen, alkyl, naphthenic base, aryl and heterocyclic group. The preparation method comprises that: an alkyne substrate I and N-fluorobenzenesulfonimide II are subjected to a fluorine amination reaction in an anhydrous organic solvent under a basic condition in the presence of a silver catalyst, wherein the reaction formula is shown in the description, R1-R5 are respectively and independently selected from hydrogen, alkyl, naphthenic base, aryl and heterocyclic group, and R6 is selected from tert-butyl. According to the present invention, a series of fluorinated isoquinoline compounds can be prepared with simple operations under mild reaction conditions; the preparation method has advantages of low cost, good substrate compatibility and the like; and sufficient guarantee can be provided for activity screening of the fluorinated isoquinoline compounds, and wide applications of the fluorinated isoquinoline compounds in the fields of medicine, pesticides and the like can be promoted.

Description

Fluoro isoquinoline compound and preparation method thereof
Technical field
The present invention relates to class fluoro isoquinoline compound and preparation method thereof, belong to technical field of organic synthesis.
Background technology
Isoquinoline 99.9 can be widely used in the field such as medicine, agricultural chemicals, can manufacture medicine and efficient pesticides, can be made into pyridine carboxylic acid after oxidation, as intermediate and the GC stationary liquid of synthetic drugs, dyestuff, sterilant.Isoquinilone derivatives is extensively present in occurring in nature, and morphinane alkaloid known at present has kind more than 1000, is a class maximum in known organism alkali.They are parent nucleus mainly with isoquinoline 99.9 or tetrahydroisoquinoline, can be subdivided into again iloquinoline derivative, benzylisoquinoline class, Dibenzylisoquinolinealkaloids, the fragrant class of Ah flutterring, proto-berberine, protopine class, ipecac bases, α-nine classes such as naphthalene phenanthridines class and opiates according to linking group.Many medicines are had to be the derivative of isoquinoline 99.9.Famous isoquinoline alkaloid Papaverine, is still important spasmolytic so far.Alchol of antimelancholic ' Nomifensin ' and antischistosomal drug praziquantel derive from tetrahydroisoquinoline.
Isoquinoline structure is one of modal structure fragment in natural product and drug molecule.In a lot of molecular structures, all contain the skeleton unit of isoquinoline 99.9, they often have good biological activity and medical value.As TMC-120 has very strong antibacterial and anti-proliferate ability, the muriate of Berberine is proved the effect having good anti-tumor activity and inhibiting HIV and copy:
Research shows, is incorporated into by fluorine atom in isoquinoline structure, greatly can improve the activity of medicine, improves drug effect; Some fluoro isoquinoline compounds to a lot of physiological maladies, as reduction intraocular pressure preparation, myosin inhibitor, there is good pharmaceutical activity the aspects such as anti-proliferative drugs, and most compound is all admitted in the middle of patent, as:
But because the method for current synthesizing fluoro isoquinoline compound is few, and it is loaded down with trivial details to there is route, substrate compatibility is bad, the problems such as condition is harsh, make the limited amount of the fluoro isoquinoline compound that can carry out screening active ingredients, so that hinder the applied research of this compounds in fields such as medicine, agricultural chemicals.
Summary of the invention
For the problems referred to above that prior art exists, the object of this invention is to provide that a kind of synthetic route is simple, reaction conditions is gentle, the compatible good method preparing fluoro isoquinoline compound of substrate and the class fluoro isoquinoline compound that obtained by the method, ensure for the screening active ingredients carrying out fluoro isoquinoline compound provides sufficient, to impel this compounds in the widespread use in the fields such as medicine, agricultural chemicals.
Fluoro isoquinoline compound of the present invention, has following general structure:
r in general formula 1~ R 5independently be selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic radical.
As a kind of preferred version, the R in general formula 1~ R 4all be selected from hydrogen, R 5be selected from alkyl, cycloalkyl or aryl.
As a kind of preferred version, the R in general formula 1~ R 4form heterocyclic radical, R 5be selected from alkyl, cycloalkyl or aryl.
Prepare a method for described fluoro isoquinoline compound, it is characterized in that: under silver-colored class catalyzer and alkaline condition, in anhydrous organic solvent, carry out fluorine amination reaction by the two benzsulfamide II of alkynes substrate I and N-fluoro, its reaction formula is as follows:
R in formula 1~ R 5independently be selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic radical, R 6be selected from the tertiary butyl.
As a kind of preferred version, described silver-colored class catalyzer is silver salt or elemental silver.
As further preferred version, described silver salt is Silver Nitrate, silver nitrite, trifluoro-methane sulfonic acid silver, silver tetrafluoroborate, Silver monoacetate or silver fluoride.
As a kind of preferred version, described alkaline condition refers under mineral alkali effect.
As further preferred version, described mineral alkali is Quilonum Retard, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate or cesium carbonate.
As a kind of preferred version, described organic solvent is N, the mixed solvent of any one or more than two kinds in N-N,N-DIMETHYLACETAMIDE, DMF, dimethyl sulfoxide (DMSO), ether, dioxane, ethylene glycol, dme, methyl-phenoxide, acetone, benzene,toluene,xylene.
As further preferred version, described organic solvent is N,N-dimethylacetamide, DMF or dimethyl sulfoxide (DMSO).
As a kind of preferred version, the temperature of carrying out fluorine amination reaction is 10 ~ 100 DEG C, more preferably 15 ~ 60 DEG C.
As a kind of preferred version, silver-colored class catalyst levels is 1 ~ 300mol% of alkynes substrate; The two benzsulfamide consumption of N-fluoro is 100 ~ 1000mol% of alkynes substrate.
As further preferred version, silver-colored class catalyst levels is 5 ~ 50mol% of alkynes substrate; The two benzsulfamide consumption of N-fluoro is 100 ~ 300mol% of alkynes substrate.
Compared with prior art, the present invention has following beneficial effect:
(1) the present invention uses the two benzsulfamide of N-fluoro as fluorination reagent, under the reaction conditions of gentleness, by simple operation, can realize the synthesis of fluoro isoquinoline compound;
(2) preparation method of the present invention also have that cost is low, the compatible advantage such as good of substrate, a series of fluoro isoquinoline compound can be obtained by the inventive method, can be the screening active ingredients carrying out fluoro isoquinoline compound and sufficient guarantee is provided, impel this compounds in the widespread use in the fields such as medicine, agricultural chemicals.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1: preparation
By the AgNO of 3.4mg (0.02mmol) 3, 7.4mg (0.1mmol) Li 2cO 3, 47.5mg (0.15mmol) the two benzsulfamide (NFSI) of N-fluoro add in reaction tubes, add the N,N-dimethylacetamide of 1.5mL, then add 24.1mg (0.1mmol) alkynes substrate stirring reaction 5 hours at 30 DEG C; Add water, with extracted with diethyl ether, combining extraction liquid, concentrated, column chromatography, with ethyl acetate and sherwood oil gradient elution, obtains 17.7mg product yield is 87%.
1H NMR(400MHz,CDCl 3)：9.07(s,1H),8.03(d,J=8.4Hz,1H),7.94(d,J=8.4Hz,1H),7.71(dd,J=7.2,7.2Hz,1H),7.57(dd,J=7.2,7.2Hz,1H),3.00(dt,J=8.0,2.4Hz,2H),1.79(tt,J=8.0,7.6Hz,2H),1.43(tq,J=7.6,7.6Hz,2H),0.96(q,J=7.6Hz,3H)；
13C NMR(100MHz,CDCl 3)：152.2(d,J=255.7Hz),147.2(d,J=6.1Hz),140.7(d,J=16.0Hz),130.3,128.8(d,J=2.3Hz),126.9,126.8(d,J=2.3Hz),126.5(d,J=16.7Hz),119.3(d,J=4.5Hz),31.2,30.7,22.5,13.9；
19F NMR(376MHz,CDCl 3)：-140.7(d,J=2.4Hz)；
HRMS:m/z(EI)calculated[M] +：203.1110,measured:203.1114。
Embodiment 2: preparation
By the AgNO of 3.4mg (0.02mmol) 3, 7.4mg (0.1mmol) Li 2cO 3, 47.5mg (0.15mmol) the two benzsulfamide (NFSI) of N-fluoro add in reaction tubes, add the N,N-dimethylacetamide of 1.5mL, then add 26.1mg (0.1mmol) alkynes substrate stirring reaction 6 hours at 30 DEG C; Add water, with extracted with diethyl ether, combining extraction liquid, concentrated, column chromatography, with ethyl acetate and sherwood oil gradient elution, obtains 19.4mg product yield is 87%.
1H NMR(400MHz,CDCl 3)：9.13(s,1H),8.12(d,J=8.4Hz,1H),8.10(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,1H),7.73(dd,J=8.0,7.2Hz,1H),7.61(t,J=7.2Hz,1H),7.52(d,J=7.2Hz,2H),7.42(t,J=7.2Hz,1H)；
13C NMR(100MHz,CDCl 3)：132.3(d,J=262.5Hz),147.6(d,J=6.1Hz),136.6(d,J=10.6Hz),135.7(d,J=5.4Hz),130.6(d,J=1.5Hz),,129.4(d,J=2.3Hz),128.9(d,J=6.0Hz),128.5,128.4,127.8,127.3(d,J=16.7Hz),126.9(d,J=1.5Hz),119.9(d,J=5.3Hz)；
19F NMR(376MHz,CDCl 3)：.-137.7(s)；
HRMS:m/z(EI)calculated[M] +：223.0797，measured:223.0795。
Embodiment 3: preparation
By the AgNO of 3.4mg (0.02mmol) 3, 7.4mg (0.1mmol) Li 2cO 3, 95.0mg (0.15mmol) the two benzsulfamide (NFSI) of N-fluoro add in reaction tubes, add the N,N-dimethylacetamide of 1.5mL, then add 22.5mg (0.1mmol) alkynes substrate stirring reaction 7 hours at 60 DEG C; Add water, with extracted with diethyl ether, combining extraction liquid, concentrated, column chromatography, with ethyl acetate and sherwood oil gradient elution, obtains 10.5mg product yield is 56%.
1H NMR(400MHz,CDCl 3)：8.91(s,1H),8.00(d,J=8.4Hz,1H),7.90(d,J=8.0Hz,1H),7.70(dd,J=8.4,8.0Hz,1H),7.53(dd,J=8.0,8.0Hz,1H),2.54-2.43(m,1H),1.22-1.15(m,2H),1.09-1.01(m,2H)；
13C NMR(100MHz,CDCl 3)：153.7(d,J=254.3Hz),147.3(d,J=5.9Hz),140.8(d,J=14.1Hz),130.4,128.1(d,J=2.2Hz),126.9(d,J=2.2Hz),126.5,126.2(d,J=16.4Hz),118.8(d,J=4.5Hz),9.9,8.5；
19F NMR(376MHz,CDCl 3)：.-145.3(s)；
HRMS:m/z(ESI)calculated[M+H] +：188.0870，measured:188.0872。
Embodiment 4: preparation
By the AgNO of 3.4mg (0.02mmol) 3, 7.4mg (0.1mmol) Li 2cO 3, 95.0mg (0.15mmol) the two benzsulfamide (NFSI) of N-fluoro add in reaction tubes, add the N,N-dimethylacetamide of 1.5mL, then add 31.2mg (0.1mmol) alkynes substrate stirring reaction 7 hours at 60 DEG C; Add water, with extracted with diethyl ether, combining extraction liquid, concentrated, column chromatography, with ethyl acetate and sherwood oil gradient elution, obtains 14.0mg product yield is 51%.
1H NMR(400MHz,CDCl 3)：9.37(s,1H),8.93(s,1H),8.35(d,J=8.8Hz,1H),8.22(d,J=8.0Hz,2H),8.04(d,J=8.4Hz,1H),7.91(dd,J=8.0,7.2Hz,1H),7.61(dd,J=7.6,7.2Hz,1H),7.56(dd,J=8.0,7.2Hz,2H),7.47(dd,J=7.6,7.2Hz,1H)；
13C NMR(100MHz,CDCl 3)：151.6,151.0(d,J=266.5Hz),149.6,141.6(d,J=13.4Hz),138.5(d,J=10.4Hz),136.9(d,J=1.5Hz),135.2(d,J=6.0Hz),133.0,129.8,129.3,129.2,129.1,128.8,128.6,127.1,122.7；
19F NMR(376MHz,CDCl 3)：.-141.6(s)；
MS:m/z(EI)calculated[M] +：274.1,measured:274.0.Anal.calcd.for C 18H 11N 2F:(%)C78.82,H4.04,N10.21；measured:C78.70,H4.22 N10.14。
Finally be necessary described herein: above embodiment is only for being described in further detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.

Claims (8)

1. a preparation method for fluoro isoquinoline compound, described fluoro isoquinoline compound has following general structure:
r in general formula 1~ R 5independently be selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic radical; It is characterized in that: described preparation method is under silver-colored class catalyzer and alkaline condition, in anhydrous organic solvent, carry out fluorine amination reaction by the two benzsulfamide II of alkynes substrate I and N-fluoro, its reaction formula is as follows:
R in reaction formula 1~ R 5independently be selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic radical, R 6be selected from the tertiary butyl;
Described silver-colored class catalyzer is silver salt or elemental silver; Described alkaline condition refers under mineral alkali effect; Described organic solvent is N, the mixed solvent of any one or more than two kinds in N-N,N-DIMETHYLACETAMIDE, DMF, dimethyl sulfoxide (DMSO), ether, dioxane, ethylene glycol, dme, methyl-phenoxide, acetone, benzene,toluene,xylene.
2. preparation method according to claim 1, is characterized in that: the R in general formula 1~ R 4all be selected from hydrogen, R 5be selected from alkyl, cycloalkyl or aryl.
3. preparation method according to claim 1, is characterized in that: the R in general formula 1~ R 4form heterocyclic radical, R 5be selected from alkyl, cycloalkyl or aryl.
4. preparation method according to claim 1, is characterized in that: described silver salt is Silver Nitrate, silver nitrite, trifluoro-methane sulfonic acid silver, silver tetrafluoroborate, Silver monoacetate or silver fluoride.
5. preparation method according to claim 1, is characterized in that: described mineral alkali is Quilonum Retard, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate or cesium carbonate.
6. preparation method according to claim 1, is characterized in that: described organic solvent is N,N-dimethylacetamide, DMF or dimethyl sulfoxide (DMSO).
7. preparation method according to claim 1, is characterized in that: the temperature of carrying out fluorine amination reaction is 10 ~ 100 DEG C.
8. preparation method according to claim 1, is characterized in that: silver-colored class catalyst levels is 1 ~ 300mol% of alkynes substrate; The two benzsulfamide consumption of N-fluoro is 100 ~ 1000mol% of alkynes substrate.
CN201210194986.1A 2012-06-13 2012-06-13 Fluorinated isoquinoline compounds and preparation method thereof Expired - Fee Related CN103483255B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210194986.1A CN103483255B (en) 2012-06-13 2012-06-13 Fluorinated isoquinoline compounds and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210194986.1A CN103483255B (en) 2012-06-13 2012-06-13 Fluorinated isoquinoline compounds and preparation method thereof

Publications (2)

Publication Number Publication Date
CN103483255A CN103483255A (en) 2014-01-01
CN103483255B true CN103483255B (en) 2015-02-18

Family

ID=49823906

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210194986.1A Expired - Fee Related CN103483255B (en) 2012-06-13 2012-06-13 Fluorinated isoquinoline compounds and preparation method thereof

Country Status (1)

Country Link
CN (1) CN103483255B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017097928A1 (en) * 2015-12-08 2017-06-15 Universität Zu Köln Cpap-tubulin module
CN105541713B (en) * 2016-01-26 2018-04-06 湖南科技大学 Isoquinoline compound and synthetic method thereof
CN105503722A (en) * 2016-01-26 2016-04-20 湖南科技大学 Method for synthesizing isoquinoline compound
CN106316949B (en) * 2016-08-19 2019-06-28 中国科学院上海有机化学研究所 [18F] fluorine label isoquinoline compound and preparation method thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2265270A1 (en) * 2008-02-04 2010-12-29 OSI Pharmaceuticals, Inc. 2-aminopyridine kinase inhibitors
CN101265231B (en) * 2008-05-08 2011-02-09 复旦大学 Method for preparing isoquinoline-N-oxide
CN101747271B (en) * 2010-01-21 2012-10-17 复旦大学 Method for preparing polysubstituted isoquinoline compounds

Also Published As

Publication number Publication date
CN103483255A (en) 2014-01-01

Similar Documents

Publication Publication Date Title
CN103483255B (en) Fluorinated isoquinoline compounds and preparation method thereof
CN105669503A (en) Trifluoromethylthiolation reagent and its preparation method and use in asymmetric trifluoromethylthiolation reaction
CN104803964A (en) Multi-substituent isocoumarin derivative and preparation method thereof
CN103910671A (en) Preparation method for vismodegib and intermediate of vismodegib
CN105330598A (en) Preparing method for pirfenidone
CN104163786A (en) Method for preparing 5-methyl-3-bromomethylpyridine hydrobromide
CN103641674B (en) Method for preparing diaryl sulfone
CN112645871B (en) N-CF 2 H-1, 2-dihydroSynthesis method of pyridine-2-ketone compound
CN104478799B (en) The preparation method of 1,4-diallyl isoquinolin
CN103483337B (en) Fluorinated isoquinoline [a] pyrrole compounds and preparation method thereof
CN107011288A (en) A kind of preparation method of aripiprazole intermediate 1 (2,3 dichlorophenyl) piperazine hydrochloride
CN103232345A (en) Synthesis method of 8-hydroxyl ethyl caprylate
CN109476649A (en) Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes
CN103709030A (en) Environmentally-friendly preparation method of ciprofibrate
CN109020895B (en) Synthesis method of metal-catalyzed 1-benzylamino-substituted benzimidazole
CN103265559B (en) Replace three ring benzoquinone compounds and preparation method thereof and application
CN103450184A (en) Salt of scoulerine derivatives
CN105418507A (en) Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine
CN106117203B (en) A kind of synthetic method of 3 arylthio Imidazoheterocyclic compounds
CN105001042A (en) Preparing method for benzenyl trifluoride class compound
CN105753910A (en) Preparation method of canagliflozin intermediate
CN105566435B (en) A kind of oleanolic acid derivate and its production and use
CN107793420A (en) A kind of synthetic method of 3,4 dihydro 2H pyrans [3,2 b] pyridines
CN104761489A (en) Method for preparing etoricoxib and pharmaceutically acceptable salt thereof
CN110003080B (en) Selenium-containing compound and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150218

CF01 Termination of patent right due to non-payment of annual fee